Cycloalkyl-containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof

ABSTRACT

The present invention discloses compounds of Formula (I), 
                         
and pharmaceutically acceptable salts thereof, which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcohol steatohepatitis disease (NASH).

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/721,214, filed on Aug. 22, 2018. The entire teachings of the above applications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to compounds and pharmaceutical compositions useful as ASK-1 inhibitors. Specifically, the present invention relates to compounds useful as inhibitors of ASK-1 and methods for their preparation and use.

BACKGROUND OF THE INVENTION

Apoptosis signal-regulating kinase 1 (ASK-1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK, MAP3K) family, which when activated phosphorylates downstream MAP kinase kinases (MAPKK, MAP2K), which in turn activate MAP kinases (MAPK). MAPKs elicit a response by phosphorylating cellular substrates, thus regulating the activity of transcription factors that ultimately control gene expression. Specifically ASK-1, also known as MAPKKK5, phosphorylates MAPKK4/MAPKK7 or MAPKK3/MAPKK6, which subsequently phosphorylates and activates the c-Jun N-terminal protein kinase (JNK) and p38 MAPKs, respectively (H. Ichijo, et al., Cell Comm. Signal 2009, 7, 1-10; K. Takeda, et al., Annu. Rev. Pharmacol. Toxicol. 2008, 48, 199-225; H. Nagai, et al., J. Biochem. Mol. Biol. 2007, 40, 1-6). Activation of the JNK and p38 pathways triggers a downstream stress response such as apoptosis, inflammation, or differentiation (H. Ichijo, et al., Science 1997, 275, 90-94; K. Takeda, et al., J. Biol. Chem. 2000, 275, 9805-9813; K. Tobiume, et al., EMBO Rep. 2001, 2, 222-228; K. Sayama et al., J. Biol. Chem. 2001, 276, 999-1004).

The activity of ASK-1 is regulated by thioredoxin (Trx), which binds to the N-terminal end of ASK-1 (M. Saitoh, et al., EMBO J. 1998, 17, 2596-2606). ASK-1 is activated succeeding autophosphorylation at Thr838 in response to environmental stimuli including oxidative stress, lipopolysaccharides (LPS), reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, an increase in cellular calcium ion concentrations, Fas ligand, and various cytokines such as tumor necrosis factor (TNF) (H. Nishitoh, et al., Genes Dev. 2002, 16, 1345-1355; K. Takeda, et al., EMBO Rep. 2004, 5, 161-166; A. Matsuzawa, et al., Nat. Immunol. 2005, 6, 587-592).

ASK-1 has been associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease, metabolic disorders, and acute and chronic liver diseases (R. Hayakawa, et al., Proc. Jpn. Acad., Ser. B 2012, 88, 434-453).

More specifically, ASK-1 has been associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcohol steatohepatitis (NASH). In a mouse model, high fat diets have caused induction of hepatic steatosis, ultimately causing fat accumulation and fatty acid oxidation. This led to the generation of ROS which caused hepatocyte dysfunction and death (S. K. Mantena, et al., Free Radic. Biol. Med. 2008, 44, 1259-1272; S. K. Mantena, et al., Biochem. 1 2009, 417, 183-193). Moreover, TNF was shown to be critical for apoptosis of hepatocytes through the ASK-1-JNK pathway, and TNF deficient mice showed reduced hepatic steatosis and fibrosis (W. Zhang, et al., Biochem. Biophys. Res. Commun. 2010, 391, 1731-1736).

Small molecule compounds which act as ASK-1 inhibitors have been disclosed in the following publications: WO 2008/016131, WO 2009/027283, WO 2009/0318425, WO 2009/123986, US 2009/0318425, WO 2011/041293, WO 2011/097079, US 2011/0009410, G. P. Volynets, et al., J. Med. Chem. 2011, 54, 2680-2686, WO 2012/003387, WO 2012/011548, WO 2012/080735, Y. Terao, et al., Bioorg. Med. Chem. Lett. 2012, 22, 7326-7329, WO 2013/112741, G. P. Volynets, et al., Eur. J. Med. Chem. 2013, 16, 104-115, US 2014/0018370, WO 2014/100541, WO 2015/095059, WO 2016/049069, WO 2016/049070.

There is a need for the development of ASK-1 inhibitors for the treatment and prevention of disease. The present invention has identified compounds which inhibit ASK-1 as well as methods of using these compounds to treat disease.

SUMMARY OF THE INVENTION

The present invention relates to compounds and pharmaceutical compositions useful as ASK-1 inhibitors. Specifically, the present invention relates to compounds useful as inhibitors of ASK-1 and methods for their preparation and use. In addition, the present invention includes the process for the preparation of the said compounds.

In its principal aspect, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or ester thereof:

wherein

-   R¹ is an optionally substituted heteroaryl, preferably an optionally     substituted 5-membered heteroaryl, such as one of the groups below:

-   -   wherein R₄ is selected from the group consisting of:     -   1) Hydrogen;     -   2) Optionally substituted —C₁-C₈ alkyl;     -   3) Optionally substituted —C₂-C₈ alkenyl;     -   4) Optionally substituted —C₂-C₈ alkynyl;     -   5) Optionally substituted —C₃-C₈ cycloalkyl;     -   6) Optionally substituted aryl;     -   7) Optionally substituted arylalkyl;     -   8) Optionally substituted heterocycloalkyl;     -   9) Optionally substituted heteroaryl; and     -   10) Optionally substituted heteroarylalkyl;

is selected from wherein

-   -   X² and X³ are each independently selected from N or C(R⁵);     -   R⁵ and R⁶ are each independently selected from the group         consisting of:     -   1) Hydrogen;     -   2) Halogen;     -   3)—NO₂;     -   4) Cyano;     -   5) Optionally substituted —C₁-C₈ alkyl;     -   6) Optionally substituted —C₃-C₈ cycloalkyl; and     -   7) Optionally substituted 3- to 8-membered heterocycloalkyl;

-   X¹ is N or C(R¹¹), R¹¹ is hydrogen, halogen or optionally     substituted alkoxy;

is selected from —C₃-C₈ cycloalkyl and —C₄-C₈ cycloalkenyl, preferably cyclopropyl, cyclobutyl, cyclopentenyl or cyclohexenyl, each of which is optionally substituted with one or more substituents which are not R³; R² is selected from the group consisting of:

-   -   1) Hydrogen;     -   2) Halogen;     -   3) —NO₂;     -   4) Cyano;     -   5) Optionally substituted —C₁-C₈ alkyl;     -   6) Optionally substituted —C₂-C₈ alkenyl;     -   7) Optionally substituted —C₂-C₈ alkynyl;     -   8) Optionally substituted —C₃-C₈ cycloalkyl;     -   9) Optionally substituted aryl;     -   10) Optionally substituted arylalkyl;     -   11) Optionally substituted 3- to 8-membered heterocycloalkyl;     -   12) Optionally substituted heteroaryl;     -   13) Optionally substituted heteroarylalkyl;     -   14) —N(R⁷)(R⁸);     -   15) —S(O)₂N(R⁷)(R⁸);     -   16) —N(R⁷)C(O)(R⁸); and     -   17) —N(R⁷)S(O)₂(R⁸);

-   R³ is selected from the group consisting of:     -   1) —NO₂;     -   2) Cyano;     -   3) —N(R⁷)(R⁸);     -   4) —N(R⁹)C(O) N(R⁷)(R⁸);     -   5) —N(R⁷)C(O)(R⁸);     -   6) —N(R⁷)C(O)₂(R⁸);     -   7) —N(R⁹) S(O)₂N(R⁷)(R⁸);     -   8) —N(R⁷)S(O)₂(R⁸);     -   9) —C(O)₂ (R⁷);     -   10) —C(O)N(R⁷)(R⁸);     -   11) —C(O)N(R⁷)S(O)₂(R⁸);     -   12) —CH₂(O)C(O)₂(R⁷);     -   13) —CH₂(O)C(O)N(R⁷)(R⁸);     -   14) Optionally substituted —C₁-C₈ alkyl;     -   15) Optionally substituted —C₂-C₈ alkenyl;     -   16) Optionally substituted —C₂-C₈ alkynyl;     -   17) Optionally substituted —C₃-C₈ cycloalkyl;     -   18) Optionally substituted aryl;     -   19) Optionally substituted arylalkyl;     -   20) Optionally substituted 3- to 8-membered heterocycloalkyl;     -   21) Optionally substituted heteroaryl; and     -   22) Optionally substituted heteroarylalkyl;         wherein R⁷, R⁸, and R⁹ are independently selected from the group         consisting of hydrogen, —C₁-C₈ alkyl, —C₃-C₈ cycloalkyl, 3- to         8-membered heterocycloalkyl, aryl, and heteroaryl, all of which         are optionally substituted with 1-3 substituents selected from         halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl         amide, —CN, alkoxy, —CF₃, aryl, and heteroaryl. Alternatively,         R⁷ and R⁸ are taken together with the nitrogen to which they are         attached to form a heterocyclic.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, solvate, hydrate or combination thereof, in combination with a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present invention provides a method for the prevention or treatment of an ASK-1 mediated disease or condition. The method comprises administering a therapeutically effective amount of a compound of Formula (I). The present invention also provides the use of a compound of Formula (I) for the preparation of a medicament for the prevention or treatment of an ASK-1 mediated disease or condition. Such diseases include autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease, metabolic disorders, and acute and chronic liver diseases.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is a compound represented by Formula (I) as described above, or a pharmaceutically acceptable salt or ester thereof.

In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, wherein

is selected from:

wherein each of the above shown groups is optionally substituted when possible, and each R⁵ and R⁶ are as previously defined.

In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, wherein

is

each of which is optionally further substituted.

In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, wherein R₁ is selected from the groups below:

and R⁴ is selected from:

wherein each of the above shown groups is optionally substituted.

In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, wherein R² is selected from the groups below:

wherein each of the above shown groups is optionally substituted.

In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, wherein

is selected from the groups below:

wherein each of the above shown groups is optionally substituted.

In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, wherein R³ is selected from:

In one embodiment, the invention provides a compound represented by Formula (IIa), or (IIb), or a pharmaceutically acceptable salt or ester thereof:

wherein R³, R⁴,

and X¹ are as previously defined.

In another embodiment, the invention provides a compound represented by Formula (IIIa) or (IIIb), or a pharmaceutically acceptable salt or ester thereof:

wherein R³ and R⁴ are as previously defined.

Representative compounds of the invention include, but are not limited to, the following compounds (compound 1 to compound 60 in Table 1) according to Formula (IIIa), and pharmaceutically acceptable salts thereof, wherein R³ and R⁴ are delineated for each compound in Table 1.

TABLE 1 compound R³ R⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

Representative compounds of the invention include, but are not limited to, the following compounds (compound 61 to compound 120 in Table 2) according to Formula (IIIb), and pharmaceutically acceptable salts thereof, wherein R³ and R⁴ are delineated for each compound in Table 2.

TABLE 2 compound R³ R⁴ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

In another embodiment, the invention provides a compound represented by Formula (IVa) or (IVb), or a pharmaceutically acceptable salt or ester thereof:

wherein R³ and R⁴ are as previously defined.

Representative compounds of the invention include, but are not limited to, the following compounds (compound 121 to compound 180 in Table 3) according to Formula (IVa), and pharmaceutically acceptable salts thereof, wherein R³ and R⁴ are delineated for each compound in Table 3.

TABLE 3 compound R³ R⁴ 121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

Representative compounds of the invention include, but are not limited to, the following compounds (compound 181 to compound 240 in Table 4) and pharmaceutically acceptable salts thereof, according to Formula (IVb), wherein R³ and R⁴ are delineated for each compound in Table 4.

TABLE 4 compound R³ R⁴ 181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

In another embodiment, the invention provides a compound represented by Formula (Va) or (Vb), or a pharmaceutically acceptable salt or ester thereof:

wherein R³ and R⁴ are as previously defined.

Representative compounds of the invention include, but are not limited to, the following compounds (compound 241 to compound 300 in Table 5) according to Formula (Va), and pharmaceutically acceptable salts thereof, wherein R³ and R⁴ are delineated for each compound in Table 5.

TABLE 5 compound R³ R⁴ 241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

Representative compounds of the invention include, but are not limited to, the following compounds (compound 301 to compound 360 in Table 6) according to Formula (Vb), and pharmaceutically acceptable salts thereof, wherein R³ and R⁴ are delineated for each compound in Table 6.

TABLE 6 compound R³ R⁴ 301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

In one embodiment, the invention provides a compound represented by Formula (VIa), or (VIb), or (VIc), or a pharmaceutically acceptable salt or ester thereof:

Wherein R¹, R², R³, and X¹ are as previously defined.

In one embodiment, the invention provides a compound represented by Formula (VIIa), or (VIIb), or (VIIc), or a pharmaceutically acceptable salt or ester thereof:

Wherein R¹, R², R³, and X¹ are as previously defined.

In one embodiment, the invention provides a compound represented by Formula (VIIIa), or (VIIIb), or a pharmaceutically acceptable salt or ester thereof:

Wherein R², R³, R⁴, and X¹ are as previously defined.

In certain embodiments, the present invention provides a method for the prevention or treatment of an ASK-1 mediated disease or condition. The method comprises administering a therapeutically effective amount of a compound of Formula (I). The present invention also provides the use of a compound of Formula (I) for the preparation of a medicament for the treatment of an ASK-1 mediated disease or condition.

In certain embodiments, the ASK-1 mediated disease or condition is an autoimmune disorder, a neurodegenerative disorder, an inflammatory disease, chronic kidney disease, renal disease, cardiovascular disease, a metabolic disease, or an acute or chronic liver disease.

In certain embodiments, the chronic liver disease is primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or alpha 1-antitrypsin deficiency. In certain embodiments, the gastrointestinal disease is inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, or microscopic colitis.

In certain embodiments, the renal disease is diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, or polycystic kidney disease.

In certain embodiments, the cardiovascular disease is atherosclerosis, arteriosclerosis, reperfusion/ischemia in stroke, cardiac hypertrophy, respiratory diseases, heart attacks, myocardial ischemia.

In certain embodiments, the metabolic disease is insulin resistance, Type I and Type II diabetes, or obesity.

In certain embodiments, the chronic kidney disease is polycystic kidney disease, pyelonephritis, kidney fibrosis and glomerulonephritis.

Yet a further aspect of the present invention is a process of making any of the compounds delineated herein employing any of the synthetic means delineated herein.

Definitions

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

The term “alkyl” as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals. “C₁-C₃ alkyl,” “C₁-C₆ alkyl,” “C₁-C₁₀ alkyl”C₂-C₄ alkyl,” or “C₃-C₆ alkyl,” refer to alkyl groups containing from one to three, one to six, one to ten carbon atoms, 2 to 4 and 3 to 6 carbon atoms respectively. Examples of C₁-C₈ alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C₂-C₁₀ alkenyl,” “C₂-C₈ alkenyl,” “C₂-C₄ alkenyl,” or “C₃-C₆ alkenyl,” refer to alkenyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. “C₂-C₁₀ alkynyl,” “C₂-C₈ alkynyl,” “C₂-C₄ alkynyl,” or “C₃-C₆ alkynyl,” refer to alkynyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term “cycloalkyl”, as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond. Preferred cycloalkyl groups include C₃-C₁₂ cycloalkyl, C₃-C₆ cycloalkyl, C₃-C₈ cycloalkyl and C₄-C₇ cycloalkyl. Examples of C₃-C₁₂ cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.

The term “cycloalkenyl”, as used herein, refers to monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond. Preferred cycloalkenyl groups include C₃-C₁₂ cycloalkenyl, C₃-C₈ cycloalkenyl or C₅-C₇ cycloalkenyl groups. Examples of C₃-C₁₂ cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl, and the like.

The term “aryl,” as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.

In accordance with the invention, aromatic groups can be substituted or unsubstituted. The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.

As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., —CH₂CH₂-phenyl. The term “substituted arylalkyl” means an arylalkyl functional group in which the aryl group is substituted. Similarly, the term “heteroarylalkyl” means a functional group wherein an alkylene chain is attached to a heteroaryl group. The term “substituted heteroarylalkyl” means a heteroarylalkyl functional group in which the heteroaryl group is substituted.

The term “alkylene” as used herein, refers to a diradical of a branched or unbranched saturated hydrocarbon chain, typically having from 1 to 20 carbon atoms (e.g. 1-10 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms). This term is exemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—), and the like.

The term “substituted” as used herein, refers to independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to, deuterium, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, N₃, protected amino, alkoxy, thioalkoxy, oxo, C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl-halo-C₁-C₁₂-alkyl,-halo-C₂-C₁₂-alkenyl,-halo-C₂-C₁₂-alkynyl,-halo-C₃-C₁₂-cycloalkyl, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl, —NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl, —C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl, —C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl, —S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl, —SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl, —NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl, —NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, methylthiomethyl, or -L′-R′, wherein L′ is C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, and R′ is aryl, heteroaryl, heterocyclic, C₃-C₁₂cycloalkyl or C₃-C₁₂cycloalkenyl. In certain embodiments, the substituents are independently selected from halo, preferably C₁ and F; C₁-C₄-alkyl, preferably methyl and ethyl; C₂-C₄-alkenyl; halo-C₁-C₄-alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; halo-C₂-C₄-alkenyl; C₃-C₆-cycloalkyl, such as cyclopropyl; —CN; —OH; NH₂; C₁-C₄-alkylamino; di(C₁-C₄-alkyl)amino; and NO₂. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted. In some cases, each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from C₁-C₄-alkyl; CF₃, —F, —Cl, —Br, —I, —OH, —NO₂, —CN, and —NH₂.

In accordance with the invention, any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group. Aromatic groups can be substituted or unsubstituted.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can also be an aliphatic group, an alicyclic group or a heterocyclic group. An “aliphatic group” is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.

The term “alicyclic” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Such alicyclic groups may be further substituted.

As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred alkoxy are (C₁-C₃) alkoxy.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term “arylthio” refers to the group R—S—, where R is as defined for aryl.

The terms “heterocyclic” or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.

It will be apparent that in various embodiments of the invention, the substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are intended to be monovalent or divalent. Thus, alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene, cycloalkynylene, arylalkylene, heteroarylalkylene and heterocycloalkylene groups are to be included in the above definitions, and are applicable to provide the Formulas herein with proper valency.

The terms “halo” and “halogen,” as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine and chlorine.

The term “optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

The term “hydrogen” includes hydrogen and deuterium. In addition, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.

In certain embodiments, the compounds of each formula herein are defined to include isotopically labelled compounds. An “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%. Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analog, and therefore exhibit a longer half-life when administered to a subject. Such compounds can synthesize using methods known in the art, for example by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable.

The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers or cis- and trans-isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be in cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.

The term “subject” as used herein refers to a mammal. A subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably the subject is a human. When the subject is a human, the subject may be referred to herein as a patient.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reaction of the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts e.g., salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, esters of C₁-C₆-alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.

The term “hydroxy activating group,” as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxyl,” as used herein, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.

The term “hydroxy protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.

The term “hydroxy prodrug group,” as used herein, refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992) and in “Prodrugs of Alcohols and Phenols” by S. S. Dhareshwar and V. J. Stella, in Prodrugs Challenges and Rewards Part-2, (Biotechnology: Pharmaceutical Aspects), edited by V. J. Stella, et al, Springer and AAPSPress, 2007, pp 31-99.

The term “amino” as used herein, refers to the group —NH₂.

The term “substituted amino” as used herein, refers to the group —NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl provided that at least one R group is not hydrogen, or a group —Y—Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl.

The term “amino protecting group” as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.

The term “leaving group” means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

As used herein, the term “pharmaceutically acceptable ester” refers to esters of the compounds formed by the process of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. “Prodrug”, as used herein means a compound, which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the Formulae of the instant invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

The term “treating”, as used herein, means relieving, lessening, reducing, eliminating, modulating, or ameliorating, i.e. causing regression of the disease state or condition. Treating can also include inhibiting, i.e. arresting the development, of an existing disease state or condition, and relieving or ameliorating, i.e. causing regression of an existing disease state or condition, for example when the disease state or condition may already be present.

The term “preventing”, as used herein means, to completely or almost completely stop a disease state or condition, from occurring in a patient or subject, especially when the patient or subject is predisposed to such or at risk of contracting a disease state or condition.

Additionally, the compounds of the present invention, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

“Solvates” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H₂O, such combination being able to form one or more hydrate.

As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar to or comparable in function and appearance to the reference compound.

The term “aprotic solvent,” as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, N Y, 1986.

The terms “protogenic organic solvent” or “protic solvent” as used herein, refer to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and variation of the reaction conditions can produce the desired isoxazole products of the present invention. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

The compounds of this invention may be modified by appending various functionalities via synthetic means delineated herein to enhance selective biological properties. Such modifications include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention Formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or Formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the Formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the Formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the Formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable Formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable Formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical Formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic Formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. All publications, patents, published patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety.

Abbreviations

Abbreviations which have been used in the descriptions of the schemes and the examples that follow are:

-   -   BOP-Cl for bis(2-oxo-3-oxazolidinyl)phosphinic chloride;     -   CDI for carbonyldiimidazole;     -   DBU for 1,8-diazabicycloundec-7-ene;     -   DCC for N,N-dicyclohexylcarbodiimide;     -   DCM for dichloromethane;     -   DIPEA for N,N-diisopropylethylamine;     -   DMAP for N,N-dimethylaminopyridine;     -   DME for 1,2-dimethoxyethane;     -   DMF for N,N-dimethyl formamide;     -   DMPU for 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone;     -   EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide         hydrochloride;     -   Et₃N for triethylamine;     -   EtOAc for ethyl acetate;     -   HATU for         1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium         3-oxid hexafluorophosphate;     -   HCl for hydrochloric acid;     -   mCPBA for meta-chloroperoxybenzoic acid;     -   NMO for N-methylmorpholine-N-oxide;     -   PhMe for toluene;     -   PyAOP for 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium         hexafluorophosphate;     -   PyBOP for benzotriazol-1-yl-oxytripyrrolidinophosphonium         hexafluorophosphate;     -   THF for tetrahydrofuran.         Synthetic Methods

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared, which are intended as an illustration only and not to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

As shown in Scheme 1, the compound of Formula (I) can be prepared from coupling of the carboxylic acid compound (1) and the amine compound (2) under suitable amide coupling conditions, wherein R¹, R², R³, X¹,

are as previously defined. Thus, a mixture of carboxylic acid compound (1) and amine compound (2) in an aprotic solvent is treated with suitable coupling reagent in the presence of organic base to form amide compound of Formula (I). The suitable coupling reagent can be, such as, but not limited to, but is not limited to, BOP-Cl, CDI, DCC, EDC, HATU, PyAOP or PyBOP and the organic base can be, such as, but not limited to, but is not limited to, Et₃N, DIPEA, pyridine or N-methyl morpholine. The aprotic solvent can be, such as, but not limited to, but is not limited to, THF, DCM and DMF. The reaction temperature is from −20° C. to 80° C.

Alternatively, the compound of Formula (I) can also be prepared by first converting carboxylic acid compound (1) to an acid chloride compound (3) and then reacting acid chloride compound (3) with amine compound (2) in the presence of an organic base (as shown in scheme 2).

Thus, the carboxylic acid compound (1) is treated with thionyl chloride or oxalyl chloride or other acid chloride formation reagent in an aprotic solvent, such as, but not limited to but is not limited to, DCM or DMF, to afford an acid chloride compound (3). Then, the acid chloride compound (3) is reacted with the amine compound (2) in an aprotic solvent, such as, but not limited to DCM or DMF in the presence of an organic base, such as, but not limited to TEA, DIPEA. DMAP or pyridine to give the compound of Formula (I).

Another alternative way to prepare the compound of Formula (I) is by first converting carboxylic acid compound (1) to mixed anhydride compound (4) and then reacting mixed anhydride compound (4) with amine compound (2) in the presence of organic base (as shown in scheme 3).

Thus, the carboxylic acid compound (1) is treated with a chloroformate reagent such as, but not limited to isobutylcloroformate in an aprotic solvent, such as, but not limited to DCM in the presence of a base such as, but not limited to TEA or DIPEA to afford mixed anhydride compound (4). Then, the mixed anhydride compound (4) is reacted with the amine compound (2) in an aprotic solvent, such as, but not limited to DCM or DMF in the presence of an organic base, such as, but not limited to TEA, DIPEA, or DMAP to give the compound of Formula (I).

Another alternative way to prepare the compound of Formula (I) is to subject carboxylic ester compound (5) and amine compound (2) in AlMe₃-mediated amide formation condition (as shown in scheme 4).

Thus, the amine compound (2) is first treated with AlMe₃ in an aprotic solvent, such as, but not limited to but is not limited to, DCM, and then reacts with carboxylic ester compound (5) to afford the compound of Formula (I). The reaction temperature is from 0° C. to 80° C.

Another alternative way to prepare the compound of Formula (I) is to subject compound (6) and amine compound (2) to carbonylation conditions (as shown in scheme 5), wherein X is selected from Cl, Br and I.

Thus, a mixture of compound (6) and amine compound (2) in an aprotic solvent is treated with suitable catalyst and ligand in the presence of base under CO atmosphere to form amide compound of Formula (I). The suitable catalyst and ligand can be, but is not limited to, Pd₂dba₃, dppf, Pd(OAc)₂ and dppp. The base can be, but is not limited to, Et₃N, DIPEA, K₂CO₃ or Cs₂CO₃. The aprotic solvent can be, but is not limited to, DMF. The reaction temperature is from 60° C. to 110° C.

Another alternative way to prepare the compound of Formula (I) is to subject bromide compound (7) and amide compound (8) to cross coupling conditions (as shown in scheme 6).

Thus, a mixture of bromide compound (7) and amide compound (8) in an aprotic solvent is treated with the suitable combination of catalysts and reagents in the presence of base under blue LED irradiation to form amide compound of Formula (I). The suitable combination of catalysts and reagents can be, but is not limited to, Ir[dF(CF₃)ppy]2(dtbpy)PF₆ in combination use with NiCl₂.dtbbpy and (Me₃Si)₃SiH. The base can be, but is not limited to, Na₂CO₃ or LiOH. The aprotic solvent can be, but is not limited to, dimethoxyethane or acetonitrile. The reaction temperature is from 20° C. to 50° C.

Another way to prepare the compound of Formula (I) is to subject boronic ester compound (9) and amide compound (10) to suitable Suzuki cross coupling conditions (as shown in scheme 7), wherein X is selected from C₁, Br and I. The catalyst can be, but is not limited to, Pd(PPh₃)₄, Pd(OAc)₂, Pd(dppf)C₁ and Pd₂dba₃. The base can be, but is not limited to, K₂CO₃, Cs₂CO₃ and K₃PO₄. The solvent can be, but is not limited to, dioxane/H₂O, THF/H₂O and DMF. The reaction temperature is from 60° C. to 110° C.

Examples

The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, Formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

Synthesis of ethyl 2-(4-fluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2-methylphenyl)cyclopropane-1-carboxylate (example 1)

Step 1

To a suspension of 5-bromo-2-fluoro-4-methylbenzoic acid (1.5 g, 6.44 mmol) in DCM (21.4 mL) was added Ghosez's reagent (1.02 mL, 7.72 mmol). The reaction was allowed to stir at room temperature for 1 h before concentration under high vac. Then the resulting crude residue was redissolved in DCM (21.4 mL), and then 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (1.31 g, 6.44 mmol) and pyridine (2.1 mL, 25.7 mmol) was added at 0° C. The reaction was allowed to stir at room temperature for overnight. Direct filtration afforded 1.61 g white solid as compound 3. The filtrate was then concentrated and purified by chromatography on silica gel using 0->5% MeOH in DCM to afford 1.03 g white solid as compound 3 (98% combined yield). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.89 (s, 1H), 8.19 (dd, J=8.3, 0.9 Hz, 1H), 8.04 (t, J=8.0 Hz, 1H), 7.95-7.87 (m, 2H), 7.48 (d, J=10.9 Hz, 1H), 5.65 (p, J=6.7 Hz, 1H), 2.43 (s, 3H), 1.44 (d, J=6.7 Hz, 6H).

6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (compound 2) was prepared according to the method disclosed in WO 2016106384.

Step 2

To a microwave vial was charged with compound 3(1.61 g, 3.86 mmol), ethyl acrylate (1.05 mL, 9.64 mmol), tris(dibenzylideneacetone)dipalladium(O) (177 mg, 0.193 mmol), tri-o-tolylphosphine (117 mg, 0.386 mmol) and triethylamine (1.6 mL, 11.57 mmol) in DMF (9.6 mL). The reaction was allowed to stir under microwave irradiation at 100° C. for 1 hour. The crude was then diluted with EtOAc and washed with aq. NH₄Cl, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->10% MeOH in DCM to afford 1.607 g white solid as compound 4 (95% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.87 (s, 1H), 8.21 (d, J=8.3 Hz, 1H), 8.10 (d, J=7.3 Hz, 1H), 8.04 (t, J=8.0 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.84 (d, J=15.9 Hz, 1H), 7.34 (d, J=11.0 Hz, 1H), 6.65 (d, J=15.8 Hz, 1H), 5.66 (p, J=6.7 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.48 (s, 3H), 1.43 (d, J=6.7 Hz, 6H), 1.27 (t, J=7.1 Hz, 3H).

Step 3

To a vial was charged with trimethylsulfonium iodide (425 mg, 1.932 mmol) and sodium hydride (77 mg, 1.932 mmol) in DMSO (2 mL). The resulting suspension was allowed to stir at room temperature for 40 min before addition of a solution of compound 4 (338 mg, 0.773 mmol) in DMSO (1.9 mL). The reaction was allowed to stir at room temperature for 5 hours before carefully quenched with water at 0° C. The reaction was then diluted with EtOAc, washed with water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->10% MeOH in DCM to afford 241.5 mg white solid as ethyl 2-(4-fluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2-methylphenyl)cyclopropane-1-carboxylate (example 1) (69% yield). LC-MS observed [M+H], 452.22, Calcd. 452.21. ¹H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.87 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.25 (d, J=11.1 Hz, 1H), 5.65 (p, J=6.7 Hz, 1H), 4.15 (d, J=7.8 Hz, 2H), 2.46-2.36 (m, 1H), 2.41 (s, 3H), 1.90-1.81 (m, 1H), 1.47 (t, J=4.7 Hz, 2H), 1.43 (d, J=6.7 Hz, 6H), 1.23 (t, J=7.1 Hz, 3H).

Synthesis of 2-(4-fluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2-methylphenyl)cyclopropane-1-carboxylic acid (example 2)

To a solution of example 1 (1.38 g, 3.07 mmol) in THF/H₂O (8 mL/2 mL) was added LiOH (110 mg, 4.60 mmol). The reaction was allowed to stir at 50° C. for 5 hours. The reaction was then cooled to room temperature and acidified by 1 M aq. HCl. The crude residue was extracted with EtOAc (X3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->5% MeOH in DCM to afford 586 mg white solid as 2-(4-fluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2-methylphenyl)cyclopropane-1-carboxylic acid (example 2) (45% yield). LC-MS observed [M+H], 424.19, Calcd. 424.18. ¹H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.74 (s, 1H), 8.87 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.25 (d, J=11.2 Hz, 1H), 5.65 (p, J=6.7 Hz, 1H), 2.42 (s, 3H), 2.40-2.36 (m, 1H), 1.78-1.66 (m, 1H), 1.43 (d, J=6.7 Hz, 6H), 1.43-1.37 (m, 2H).

Synthesis of 5-(2-(cyclopropylcarbamoyl)cyclopropyl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (example 3)

To a solution of example 2 (18.4 mg, 0.043 mmol) in DMF (0.4 mL) was added cyclopropanamine (5 mg, 0.087 mmo), HATU (33 mg, 0.087 mmol) and DIPEA (23 μL, 0.13 mmol). The reaction was allowed to stir at room temperature for overnight. The crude was directly purified by chromatography on silica gel using 0->5% MeOH in DCM to afford 12 mg white solid as 5-(2-(cyclopropylcarbamoyl)cyclopropyl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (example 3) (60% yield). LC-MS observed [M+H], 463.24, Calcd. 463.23. ¹H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.87 (s, 1H), 8.27 (d, J=4.2 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.03 (t, J=7.9 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.23 (d, J=11.1 Hz, 1H), 5.72-5.58 (m, 1H), 2.70-2.65 (m, 1H), 2.39 (s, 3H), 2.26-2.17 (m, 1H), 1.77-1.69 (m, 1H), 1.43 (d, J=6.8 Hz, 6H), 1.38-1.28 (m, 1H), 1.20-1.12 (m, 1H), 0.67-0.59 (m, 2H), 0.48-0.29 (m, 2H).

Synthesis of tert-butyl (2-(4-fluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2-methylphenyl)cyclopropyl)carbamate (example 4)

Step 1

To a suspension of example 2 (523 mg, 1.24 mmol) in toluene (6 mL) was added diphenyl phosphoryl azide (0.53 mL, 2.47 mmol) and triethylamine (0.52 mL, 3.71 mmol). The reaction was allowed to stir at room temperature for 20 hours. The reaction was carefully quenched with aq. NaHCO₃ and extracted with EtOAc (X3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->5% MeOH in DCM to afford 380.7 mg white solid as compound 5 (69% yield). ¹H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.87 (s, 1H), 8.19 (dd, J=8.3, 0.9 Hz, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.88 (dd, J=7.7, 0.9 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.26 (d, J=11.1 Hz, 1H), 5.64 (p, J=6.7 Hz, 1H), 2.63-2.55 (m, 1H), 2.42 (s, 3H), 1.97-1.89 (m, 1H), 1.74-1.65 (m, 1H), 1.65-1.57 (m, 1H), 1.43 (d, J=6.7 Hz, 6H).

Step 2

A solution of compound 5 (120 mg, 0.268 mmol) in toluene (1.3 mL) was heated at 80° C. for 1 hour before addition of tBuOH (0.26 mL, 2.68 mmol). The reaction was allowed to stir at the same temperature for overnight. The crude was concentrated and purified by chromatography on silica gel using 0->10% MeOH in DCM to afford 98.7 mg white solid as tert-butyl (2-(4-fluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2-methylphenyl)cyclopropyl)carbamate (example 4) (75% yield). LC-MS observed [M+H], 495.26, Calcd. 495.25. ¹H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.86 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.31 (s, br, 2H), 7.20 (d, J=11.2 Hz, 1H), 5.65 (p, J=6.8 Hz, 1H), 2.64-2.51 (m, 1H), 2.45 (s, 3H), 1.95-1.87 (m, 1H), 1.43 (dd, J=6.7, 1.2 Hz, 6H), 1.40 (s, 9H), 1.26-1.05 (m, 2H).

Synthesis of 3,3-difluoro-N-(2-(4-fluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2-methylphenyl)cyclopropyl)pyrrolidine-1-carboxamide (example 5)

A solution of compound 5 (19.3 mg, 0.043 mmol) in toluene (0.43 mL) was heated at 80° C. for 1 hour before addition of 3,3-difluoropyrrolidine hydrochloride (18.5 mg, 0.129 mmol) and DIPEA (30 μL, 0.172 mmol). The reaction was allowed to stir at the same temperature for overnight. The crude was concentrated and purified by chromatography on silica gel using 0->10% MeOH in DCM to afford 20.8 mg white solid as 3,3-difluoro-N-(2-(4-fluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2-methylphenyl)cyclopropyl)pyrrolidine-1-carboxamide (example 5) (92% yield). LC-MS observed [M+H], 528.24, Calcd. 528.23. ¹H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.86 (d, J=0.9 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.19 (d, J=11.1 Hz, 1H), 6.72 (d, J=3.5 Hz, 1H), 5.69-5.56 (m, 1H), 3.72-3.56 (m, 2H), 3.45 (d, J=7.9 Hz, 2H), 2.70-2.63 (m, 1H), 2.47 (s, 3H), 2.43-2.30 (m, 2H), 1.91 (s, 1H), 1.43 (d, J=6.7 Hz, 6H), 1.28-1.12 (m, 2H).

Synthesis of 2-fluoro-5-(2-(4-fluorobenzamido)cyclopropyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (example 6)

Step 1

To a solution of example 4 (98.7 mg, 0.20 mmol) in dioxane (0.4 mL) was added 4M HCl in dioxane (0.5 mL, 2.0 mmol). The reaction was allowed to stir at room temperature for overnight.

The crude reaction was concentrated and the resulting white solid was directly used in the following transformation. LC-MS observed [M+H], 395.21, Calcd. 395.20.

Step 2

To a suspension of compound 6 (26 mg, 0.066 mmol) in DCM (0.66 mL) was added DIPEA (69 μL, 0.396 mmol) and 4-fluorobenzoyl chloride (12.6 mg, 0.079 mmol) at 0° C. The reaction was allowed to stir at the same temperature for 2 hours. The crude reaction was concentrated and purified by chromatography on silica gel using 0->10% MeOH in DCM to afford 27.4 mg white solid as 2-fluoro-5-(2-(4-fluorobenzamido)cyclopropyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (example 6) (80% yield). LC-MS observed [M+H], 517.22, Calcd. 517.22. ¹H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.87 (s, 1H), 8.74 (d, J=4.5 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.94 (dd, J=8.8, 5.6 Hz, 2H), 7.89 (d, J=7.6 Hz, 1H), 7.42 (d, J=7.3 Hz, 1H), 7.32 (t, J=8.8 Hz, 2H), 7.23 (d, J=11.2 Hz, 1H), 5.66 (p, J=6.7 Hz, 1H), 3.07-2.97 (m, 1H), 2.48 (s, 3H), 2.14-2.07 (m, 1H), 1.44 (dd, J=6.7, 1.1 Hz, 6H), 1.41-1.29 (m, 2H).

Synthesis of 5-(2-((N,N-dimethylsulfamoyl)amino)cyclopropyl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (example 7)

To a suspension of compound 6 (26 mg, 0.066 mmol) in DCM (0.66 mL) was added DIPEA (69 μL, 0.396 mmol) and dimethylsulfamoyl chloride (8.5 μL, 0.079 mmol) at 0° C. The reaction was allowed to stir at room temperature for 3 days. The crude reaction was concentrated and purified by chromatography on silica gel using 0->10% MeOH in DCM to afford 27.2 mg white solid as 5-(2-((N,N-dimethylsulfamoyl)amino)cyclopropyl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (example 7) (84% yield). LC-MS observed [M+H], 502.21, Calcd. 502.20. ¹H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.86 (s, 1H), 8.20 (dd, J=8.3, 0.9 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.88 (dd, J=7.7, 0.9 Hz, 1H), 7.82 (d, J=2.5 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.21 (d, J=11.2 Hz, 1H), 5.64 (p, J=6.5 Hz, 1H), 2.72 (s, 6H), 2.61-2.57 (m, 1H), 2.47 (s, 3H), 2.20-2.09 (m, 1H), 1.43 (dd, J=6.7, 0.9 Hz, 6H), 1.29-1.12 (m, 2H).

Synthesis of tert-butyl (2-(2-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-5-methylpyridin-4-yl)cyclopropyl)carbamate (example 8)

Compound 8 was prepared in a similar way as example 4 from commercially available starting material compound 7.

To a solution of compound 8 (34.7 mg, 0.123 mmol) in DMF (0.6 mL) was added compound 2 (52.8 mg, 0.245 mmol), Pd(OAc)₂ (2.8 mg, 0.012 mmol), dppp (10.1 mg, 0.025 mmol) and triethylamine (51 μL, 0.368 mmol). The reaction was purged with CO (X3) and allowed to stir at 80° C. under 1 atm CO atmosphere for overnight. The crude was diluted with EtOAc, washed with water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->100% acetone in hex to afford 4.7 mg white solid tert-butyl (2-(2-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-5-methylpyridin-4-yl)cyclopropyl)carbamate (example 8) (8% yield). LC-MS observed [M+H], 478.26, Calcd. 478.26.

Synthesis of tert-butyl (R)-(3-(2-((6-(1-(1-hydroxypropan-2-yl)-1H-tetrazol-5-yl)pyri din-2-yl)carbamoyl)-5-methylpyridin-4-yl)cyclobutyl)carbamate (example 9)

Step 1

To a solution of tert-butyl (3-hydroxycyclobutyl)carbamate (3.98 g, 21.24 mmol) in THF (106 mL) was added PPh₃ (11.14 g, 42.5 mmol) and CBr₄ (42.09 g, 42.5 mmol). The resulting suspension was allowed to stir at room temperature for 20 hours. The reaction was diluted with 500 mL EtOAc and washed with 10% H₂O₂ (100 mL×2), aq. Na₂SO₃ (100 mL×2) and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was redissolved in EtOH (160 mL) and was chagred with a homogeneous solution of zinc chloride (11.58 g, 85 mmol) in warm EtOH (80 mL). The resulting solution was allowed to stir at for 1 hour until precipitation occurred. Filtration. The resulting filtrate was concentrated and purified by chromatography on silica gel using 0->50% EtOAc in hex to afford 2.45 g white solid as compound 10 (46% yield).

Step 2

To an 8 mL vial was charged with photocatalyst Ir[dF(CF₃)ppy]2(dtbbpy)PF₆ (73 mg, 0.065 mmol), methyl 5-bromo-2-fluoro-4-methylbenzoate (compound 7) (1.348 g, 6.53 mmol), compound 10 (2.45 g, 9.79 mmol), tris(trimethylsilyl)silane (1.691 g, 6.53 mmol) and LiOH (0.313 g, 13.06 mmol) in DME (26 mL). To a separate vial was added NiCl2.glyme (14.6 mg) and 4,4″-di-tert-butyl-2,2″-dipyridine (19 mg). The catalyst vial was sealed, purged with nitrogen, and DME (6 mL) was then added. The precatalyst solution was stirred for 5 minutes, after which, 3 mL of the solution was added into the previous reaction vessel. The reaction solution was then degassed and irridiated with a Kessil blue LED lamp for 20 hours. The crude was diluted with EtOAc, washed with water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->50% EtOAc in hex to afford 1.09 g pale yellow sticky oil as compound 11.

Step 3

To a solution of compound 11 (104.5 mg, 0.352 mmol) in DMF/EtOH (0.88 mL/0.88 mL) was added Pd(OAc)₂ (7.9 mg, 0.035 mmol), dppp (29 mg, 0.070 mmol) and K₂CO₃ (97 mg, 0.704 mmol). The reaction was purged with CO (X3) and allowed to stir at 80° C. under 1 atm CO atmosphere for overnight. The crude was diluted with EtOAc, washed with water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->40% acetone in hex to afford 48.9 mg white solid as compound 12 (42% yield).

Step 4

To a solution of AlMe₃ (2.0 M in toluene solution, 0.24 mL, 0.48 mmol) in DCM (0.4 mL) was added compound 13 (35.6 mg, 0.161 mmol) at 0° C. The reaction was allowed to stir for 20 min at the same temperature before warm to room temperature for 1 hour. Then a solution of compound 12 (27 mg, 0.081 mmol) in DCM (0.4 mL) was carefully added in the reaction. The resulting reaction was allowed to stir at 40° C. for 18 hours. The reaction was carefully quenched with 20% Rochelle's salt aq. solution at 0° C. The aq. layer was extracted by DCM (X2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->50% acetone in hex to afford 15 mg white solid as tert-butyl (R)-(3-(2-((6-(1-(1-hydroxypropan-2-yl)-1H-tetrazol-5-yl)pyridin-2-yl)carbamoyl)-5-methylpyridin-4-yl)cyclobutyl)carbamate (example 9) (37% yield). LC-MS observed [M+H], 509.26, Calcd. 509.26.

Synthesis of (R)-2-(5-(6-aminopyridin-2-yl)-1H-tetrazol-1-yl)propan-1-ol (compound 13) was illustrated as below.

Step 1

TFA (3.2 mL) was added to a solution of (R)-2-((tert-butoxycarbonyl)amino)propyl acetate (992 mg, 4.57 mmol) in DCM (6.5 mL) and the reaction was stirred for 3.5 hrs. The reaction was concentrated under reduced pressure at 45° C. until TFA was removed. Dried oil under vacuum 40° C. give crude (R)-1-acetoxypropan-2-ammonium 2,2,2-trifluoroacetate as a clear oil that was used without purification: ¹H NMR (400 MHz, DMSO-d6) δ 4.12 (dd, J=11.8, 4.1 Hz, 1H), 4.02 (dd, J=11.8, 7.1 Hz, 1H), 3.55-3.41 (m, 1H), 2.06 (s, 3H), 1.18 (d, J=6.7 Hz, 3H).

Step 2

DIPEA (3.1 mL, 17.6 mmol), a solution of (R)-1-acetoxypropan-2-ammonium 2,2,2-trifluoroacetate (1.1 g, 4.57 mmol) in DMF (5 mL), and HATU (2.0 g, 5.28 mmol) was added to a solution of 6-nitropicolinic acid (592 mg, 3.52 mmol) in DMF (6.73 mL) and the reaction was stirred overnight. The reaction was quenched with H₂O and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water (1×), brine (2×), dried (MgSO₄), filtered, and concentrated under reduced pressure. The resultant yellow gum was purified by column chromatography eluting with hexanes/EtOAc (0% EtOAc→40% EtOAc) to give (R)-2-(6-nitropicolinamido)propyl acetate (770 mg, 2.88 mmol, 82% yield) as a yellow gum: ¹H NMR (400 MHz, Chloroform-d) δ 8.57 (dd, J=7.7, 1.0 Hz, 1H), 8.39 (dd, J=8.1, 1.0 Hz, 1H), 8.23 (t, J=7.9 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 4.58-4.43 (m, 1H), 4.24 (dd, J=11.3, 4.4 Hz, 1H), 4.18 (dd, J=11.3, 5.5 Hz, 1H), 2.11 (s, 3H), 1.36 (d, J=6.8 Hz, 3H).

Step 3

To a mixture of (R)-2-(6-nitropicolinamido)propyl acetate (765 mg, 2.86 mmol) and sodium azide (298 mg, 4.58 mmol) in acetonitrile (19.1 mL) behind a blast shield at 0° C. was added Tf₂O (4.29 mL, 4.29 mmol, 1.0M solution in DCM) dropwise, and the resulting mixture was stirred for 30 min at 0° C. The cold bath was removed, and the mixture was stirred at rt for 1 h. The reaction was quenched with sat. NaHCO₃ and diluted with EtOAc. The organic layer was separated and washed with brine, dried, filtered and concentrated under reduced pressure. The resultant residue was purified by column chromatography eluting with hexanes/EtOAc (0% EtOAc→60% EtOAc) to give (R)-2-(5-(6-nitropyridin-2-yl)-1H-tetrazol-1-yl)propyl acetate (699 mg, 2.392 mmol, 84% yield) as a pale yellow solid: ¹H NMR (500 MHz, Chloroform-d) δ 8.79 (dd, J=7.8, 0.9 Hz, 1H), 8.43 (dd, J=8.1, 1.0 Hz, 1H), 8.32 (dd, J=8.4, 7.4 Hz, 1H), 6.17 (pd, J=7.0, 4.5 Hz, 1H), 4.64 (dd, J=11.8, 4.6 Hz, 1H), 4.59 (dd, J=11.7, 7.5 Hz, 1H), 1.88 (d, J=1.0 Hz, 3H), 1.82 (dd, J=6.9, 1.1 Hz, 3H).

Step 4

Pd—C (140 mg, 10% loading) was added to a solution of (R)-2-(5-(6-nitropyridin-2-yl)-1H-tetrazol-1-yl)propyl acetate (699 mg, 2.392 mmol) in MeOH (18.4 mL) and EtOAc (18.4 mL). The reaction was evacuated and backfilled with H₂ (3×) and the reaction was stirred under a balloon of H₂ overnight. The reaction was filtered through Celite, rinsing with DCM. The filtrate was concentrated under reduced pressure, dissolved in DCM, and filtered through Celite, rinsing with DCM. The filtrate was concentrated under reduced pressure to give (R)-2-(5-(6-aminopyridin-2-yl)-1H-tetrazol-1-yl)propyl acetate (575 mg, 2.192 mmol, 92% yield) as a colorless gum that solidified upon standing: ¹H NMR (500 MHz, Chloroform-d) δ 7.67-7.60 (comp, 2H), 6.66 (d, J=7.0 Hz, 1H), 6.21 (d, J=10.4 Hz, 1H), 4.67 (dd, J=11.4, 4.3 Hz, 1H), 4.30 (dd, J=11.4, 9.4 Hz, 1H), 1.84 (s, 3H), 1.70 (d, J=6.8 Hz, 3H).

Step 5

K₂CO₃ (1.1 g, 8.20 mmol) was added to a solution of (R)-2-(5-(6-aminopyridin-2-yl)-1H-tetrazol-1-yl)propyl acetate (430 mg, 1.64 mmol) in MeOH (6.6 mL) and the reaction was stirred for 30 min. The reaction was concentrated to remove MeOH and the residue was partitioned between DCM and H₂O. The layers were separated and the aqueous layer was extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give (R)-2-(5-(6-aminopyridin-2-yl)-1H-tetrazol-1-yl)propan-1-ol (compound 13)(327 mg, 1.485 mmol, 91% yield) as a yellow gum: ¹H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J=8.4, 7.3 Hz, 1H), 7.27 (dd, J=7.3, 0.8 Hz, 1H), 6.62 (dd, J=8.4, 0.8 Hz, 1H), 6.36 (s, 2H), 5.83-5.76 (m, 1H), 4.96 (t, J=5.6 Hz, 1H), 3.80 (ddd, J=11.2, 8.1, 5.9 Hz, 1H), 3.71 (dt, J=11.0, 5.3 Hz, 1H), 1.52 (d, J=6.8 Hz, 3H).

The following examples were prepared by using procedures similar to those described above:

ESIMS Ex- (M − H)⁻ or ample Structure (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆) 10

521.20 10.71 (s, 1H), 8.86 (s, 1H), 8.23- 8.13 (m, 2H), 8.02 (t, J = 8.0 Hz, 1H), 7.88 (dd, J = 7.6, 0.9 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 11.2 Hz, 1H), 5.65 (p, J = 6.7 Hz, 1H), 4.68 (q, J = 9.1 Hz, 2H), 2.73-2.66 (m, 1H), 2.46 (s, 3H), 2.09-2.00 (m, 1H), 1.43 (d, J = 6.7 Hz, 6H), 1.22-1.11 (m, 2H). 11

499.20 12

513.23 13

548.24 14

479.27 10.71 (s, 1H), 8.86 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 4.6 Hz, 1H), 7.38 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 11.2 Hz, 1H), 5.65 (p, J = 6.7 Hz, 1H), 2.87-2.80 (m, 1H), 2.43 (s, 3H), 1.97-1.87 (m, 1H), 1.43 (dd, J = 6.6, 1.6 Hz, 6H), 1.22-1.08 (m, 2H), 1.11 (s, 9H). 15

435.22 16

525.25 17

533.21 18

560.26 ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.90 (s, 1H), 8.33 (dd, J = 8.3, 0.9 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.86 (dd, J = 7.6, 0.9 Hz, 1H), 7.63 (s, 1H), 7.12 (s, 1H), 6.67 (d, J = 3.5 Hz, 1H), 5.48 (p, J = 6.7 Hz, 1H), 3.99 (s, 3H), 3.45 (dp, J = 14.1, 7.0 Hz, 2H), 2.82 (s, 3H), 2.67 (dd, J = 4.1, 2.5 Hz, 1H), 2.48 (s, 3H), 2.47-2.40 (m, 2H), 1.87 (ddd, J = 9.7, 6.4, 3.5 Hz, 1H), 1.53 (dd, J = 6.7, 1.3 Hz, 6H), 1.20 (dt, J = 9.6, 5.0 Hz, 1H), 1.03 (q, J = 6.4 Hz, 1H). 19

504.20 20

514.23 ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.90 (s, 1H), 8.32 (dd, J = 8.4, 0.9 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.86 (dd, J = 7.7, 0.9 Hz, 1H), 7.81 (s, 1H), 7.54 (s, 1H), 7.13 (s, 1H), 5.48 (p, J = 6.8 Hz, 1H), 3.98 (s, 3H), 2.74 (s, 6H), 2.49 (s, 3H), 2.17-2.04 (m, 1H), 1.53 (d, J = 6.7 Hz, 6H), 1.23 (dt, J = 9.5, 4.6 Hz, 1H), 1.06 (q, J = 6.5 Hz, 1H). 21

567.20 22

529.24 ¹H NMR (500 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.83 (s, 1H), 8.66 (d, J = 4.7 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.88 (dd, J = 8.7, 5.6 Hz, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.60 (s, 1H), 7.25 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 5.42 (p, J = 6.7 Hz, 1H), 3.93 (s, 3H), 2.92 (dt, J = 8.0, 4.0 Hz, 1H), 2.43 (s, 3H), 2.01 (ddd, J = 9.8, 6.4, 3.6 Hz, 1H), 1.46 (d, J = 6.7 Hz, 6H), 1.29 (dt, J = 9.7, 5.1 Hz, 1H), 1.15 (dt, J = 7.8, 5.8 Hz, 1H). 23

491.28 ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.90 (s, 1H), 8.33 (dd, J = 8.4, 0.9 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.86 (dd, J = 7.6, 0.9 Hz, 1H), 7.65 (d, J = 5.2 Hz, 2H), 7.12 (s, 1H), 5.48 (p, J = 6.7 Hz, 1H), 3.99 (s, 3H), 2.79 (dq, J = 8.5, 4.5 Hz, 1H), 2.45 (s, 3H), 1.90 (ddd, J = 9.7, 6.2, 3.6 Hz, 1H), 1.53 (dd, J = 6.7, 1.3 Hz, 6H), 1.25 (dt, J = 9.6, 5.2 Hz, 1H), 1.12 (s, 9H), 1.10-0.97 (m, 1H). 24

529.22 25

537.19 ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.80 (s, 1H), 8.29- 8.14 (m, 2H), 8.05 (t, J = 8.1 Hz, 1H), 7.90 (dd, J = 7.6, 0.9 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 11.2 Hz, 1H), 5.58 (d, J = 6.5 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.71 (q, J = 9.2 Hz, 2H), 3.69- 3.61 (m, 2H), 2.49 (s, 3H), 2.05 (m, 1H), 1.47 (d, J = 6.9 Hz, 3H), 1.30 (d, J = 7.2 Hz, 1H), 1.26- 1.15 (m, 1H). 26

564.23 ¹H NMR (400 MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.77 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.02 (t, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 11.2 Hz, 1H), 6.69 (d, J = 3.4 Hz, 1H), 5.67-5.46 (m, 1H), 5.05 4.80 (m, 1H), 3.63 (d, J = 9.6 Hz, 2H), 3.46 (m, J = 7.5 Hz, 2H), 2.82 (s, 3H), 2.75-2.65 (m, 1H), 2.46 (s, 3H), 1.88 (s, 1H), 1.43 (dd, J = 7.0, 1.4 Hz, 3H), 1.22 (dt, J = 9.8, 5.1 Hz, 1H), 1.14 (q, J = 6.3 Hz, 1H). 27

571.17 28

518.20 ¹H NMR (400 MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.77 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.02 (t, J = 7.9 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.23 (dd, J = 14.3, 9.2 Hz, 2H), 5.54 (d, J = 5.6 Hz, 1H), 4.93 (t, J = 5.3 Hz, 1H), 3.62 (d, J = 5.4 Hz, 1H), 2.73 (s, 6H), 2.47 (s, 3H), 2.14 (s, 1H), 1.43 (d, J = 6.9 Hz, 3H), 1.23 (dd, J = 9.8, 4.5 Hz, 1H), 1.18 (d, J = 6.6 Hz, 1H). 29

495.25 ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.77 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.02 (t, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 4.7 Hz, 1H), 7.38 (d, J = 5.7 Hz, 1H), 7.20 (d, J = 11.2 Hz, 1H), 5.55 (d, J = 6.5 Hz, 1H), 4.93 (t, J = 5.4 Hz, 1H), 3.62 (m, 2H), 2.90-2.79 (m, 1H), 2.43 (s, 3H), 1.91 (s, 2H), 1.53-1.36 (m, 3H), 1.27 (dt, J = 9.5, 5.1 Hz, 1H), 1.22-1.15 (m, 1H), 1.11 (s, 9H).

Synthesis of example 30 is illustrated in the scheme below:

Step 1

To a solution of commercially available compound 20 (1.25 g, 5.36 mmol) in DCM/tBuOH (10 mL/5 mL) was added Boc anhydride (2.34 g, 10.73 mmol) and DMAP (0.72 g, 5.9 mmol). The reaction was allowed to stir at room temperature for 3 hours. The crude was diluted with EtOAc and washed with aq. NH₄Cl and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->50% EtOAc in hexanes to afford 1.214 g colorless oil as compound 21 (78% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J=6.9 Hz, 1H), 7.41 (d, J=11.5 Hz, 1H), 2.39 (s, 3H), 1.54 (d, J=1.0 Hz, 9H).

Step 2

To a solution of compound 21 (1.093 g, 3.78 mmol) in dioxane/water (9.45 mL/2.36 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.165 g, 7.56 mmol), tetrakis(triphenylphosphine)palladium(O) (0.437 g, 0.378 mmol) and potassium carbonate (1.045 g, 7.56 mmol). The reaction was allowed to stir at 80° C. for 20 hours. The crude was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->20% MTBE in hexanes to afford 0.624 g colorless oil as compound 22 (70% yield). ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.5 Hz, 1H), 6.91 (d, J=11.4 Hz, 1H), 6.85 (dd, J=17.4, 11.0 Hz, 1H), 5.67 (dd, J=17.3, 1.2 Hz, 1H), 5.35 (dt, J=10.9, 0.9 Hz, 1H), 2.38 (s, 3H), 1.58 (s, 9H).

Step 3

To a solution of compound 22 (149 mg, 0.631 mmol) and rhodium(II) acetate dimer (13.9 mg, 0.032 mmol) in DCM (3.1 mL) was slowly added ethyl 2-diazoacetate (381 μL, 3.15 mmol) via syring pump ove 8 hours at room temperature. The crude was concentrated and purified by chromatography on silica gel using 0->30% EtOAc in hexanes to afford 97.6 mg colorless oil as compound 23 (48% yield). ¹H NMR (500 MHz, Chloroform-d) δ 7.63 (d, J=7.4 Hz, 1H), 6.79 (d, J=11.4 Hz, 1H), 3.81 (qd, J=7.2, 1.2 Hz, 2H), 2.29 (m, 1H), 2.27 (s, 3H), 2.08 (ddd, J=9.1, 8.0, 5.5 Hz, 1H), 1.67 (dt, J=7.5, 5.3 Hz, 1H), 1.51 (s, 9H), 1.33 (td, J=8.2, 5.0 Hz, 1H), 0.93 (t, J=7.1 Hz, 3H).

Step 4

To a solution of compound 23 (257 mg, 0.797 mmol) in DCM (2.8 mL) was added trifluoroacetic acid (0.31 mL, 3.99 mmol). The reaction was allowed to stir at room temperature for 16 hours. The crude was concentrated and purified by chromatography on silica gel using 0->50% EtOAc in hexanes to afford 188 mg white solid as compound 24 (89% yield). ¹H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J=7.4 Hz, 1H), 6.97 (d, J=11.5 Hz, 1H), 3.93 (q, J=7.1 Hz, 2H), 2.42 (m, 4H), 2.29-2.16 (m, 1H), 1.80 (dt, J=7.6, 5.4 Hz, 1H), 1.47 (td, J=8.3, 5.2 Hz, 1H), 1.03 (t, J=7.1 Hz, 3H).

Step 5

To a suspension of compound 24 (188 mg, 0.706 mmol) in DCM (3.5 mL) was added Ghosez's reagent (112 μL, 0.847 mmol). The reaction was allowed to stir at room temperature for 1 h before concentration under high vac. Then the resulting crude residue was redissolved in DCM (3.5 mL), and then compound 2 (172 mg, 0.847 mmol) and 2,6-lutidine (329 μL, 2.82 mmol) was added at 0° C. The reaction was allowed to stir at room temperature for overnight. The crude was diluted with EtOAc and washed with aq. NH₄Cl and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel using 0->10% MeOH in DCM to afford 272 mg white solid as example 30 (85% yield). LC-MS observed [M+H], 452.22, Calcd. 452.21. ¹H NMR (400 MHz, DMSO-d6) δ 10.66 (d, J=2.5 Hz, 1H), 8.87 (d, J=0.8 Hz, 1H), 8.21 (dd, J=8.3, 0.9 Hz, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.89 (dd, J=7.6, 0.9 Hz, 1H), 7.51 (d, J=7.4 Hz, 1H), 7.19 (d, J=11.3 Hz, 1H), 5.67 (p, J=6.6 Hz, 1H), 3.85 (qd, J=7.3, 2.1 Hz, 2H), 2.53 (m, 1H), 2.36 (s, 3H), 2.22 (td, J=8.2, 5.2 Hz, 1H), 1.61 (q, J=5.4 Hz, 1H), 1.44 (m, 7H), 1.24-1.07 (m, 1H), 0.98 (td, J=7.1, 0.8 Hz, 3H).

ASSAYS

The ability (IC₅₀) of compounds to inhibit ASK1 kinase activity was determined by HTRF® KinEASE™ Assay System.

ASK1 was purchased from Thermofisher (Catalogue #PV4011), ATP was purchased from Sigma (Catalogue #A7699), HTRF® KinEASE™ Assay System was obtained from Cisbio (Bedford, Mass.). ½ Area plate was purchased from Perkin Elmer (Catalogue # #6005560). HTRF® KinEASE™-STK is a generic method for measuring serine/threonine kinase activities using a time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay. The IC₅₀ value for each compound was determined in the presence of compound (various concentration from 0 to 10 μM) and a fixed amount of ATP and peptide substrates. The test compound, 1 uM STK3 peptide substrate, and 5 nM of ASK1 kinase are incubated with kinase reaction buffer containing 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, and 1 mM EGTA for 30 minutes. 100 uM ATP is added to start kinase reaction and incubated for 3 hours. The STK3-antibody labeled with Eu³⁺-Cryptate and 125 nM streptavidin-XL665 are mixed in a single addition with stop reagents provided by the Cisbio kit used to stop the kinase reaction. Fluorescence is detected using an Envision Multilabeled 2014 reader from PerkinElmer. The Fluorescence is measured at 615 nm (Cryptate) and 665 nm (XL665) and a ratio of 665 nm/615 nm is calculated for each well. The resulting TR-FRET is proportional to the phosphorylation level. Staurosporine was used as the positive control. IC₅₀ was determined by XLfit 5.3.

By using above method, the inhibition of ASK1 was tested for the compound of formula (I). IC₅₀ ranges are as follows: A<1 nM; 1 nM<B<10 nM; C>10 nM.

TABLE 7 Example No. IC50 1 B 2 C 3 C 4 B 5 C 6 C 7 C 8 C 9 C 10 B 11 B 12 C 13 C 14 C 15 B 16 B 17 B 18 B 19 C 20 B 21 B 22 B 23 B 24 B 25 C 26 B 27 B 28 B 29 B 30 C

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. 

What is claimed:
 1. A compound represented by Formula I or a pharmaceutically acceptable salt thereof:

wherein R₁ is selected from the following:

wherein R₄ is selected from the group consisting of: 1) Hydrogen; 2) Optionally substituted —C₁-C₈ alkyl; 3) Optionally substituted —C₂-C₈ alkenyl; 4) Optionally substituted —C₂-C₈ alkynyl; 5) Optionally substituted —C₃-C₈ cycloalkyl; 6) Optionally substituted aryl; 7) Optionally substituted arylalkyl; 8) Optionally substituted heterocycloalkyl; 9) Optionally substituted heteroaryl; and 10) Optionally substituted heteroarylalkyl;

is selected from

wherein X² and X³ are each independently selected from N or C(R⁵); R⁵ and R⁶ are each independently selected from the group consisting of: 1) Hydrogen; 2) Halogen; 3) —NO₂; 4) Cyano; 5) Optionally substituted —C₁-C₈ alkyl; 6) Optionally substituted —C₃-C₈ cycloalkyl; and 7) Optionally substituted 3- to 8-membered heterocycloalkyl; X¹ is N or C(R¹¹), R¹¹is hydrogen, halogen or optionally substituted alkoxy;

is selected from —C₃-C₈ cycloalkyl and —C₄-C₈ cycloalkenyl, each of which, is optionally substituted with one or more substituents, which are not R³; R² is selected from the group consisting of: 1) Hydrogen; 2) Halogen; 3) —NO₂; 4) Cyano; 5) Optionally substituted —C₁-C₈ alkyl; 6) Optionally substituted —C₂-C₈ alkenyl; 7) Optionally substituted —C₂-C₈ alkynyl; 8) Optionally substituted —C₃-C₈ cycloalkyl; 9) Optionally substituted aryl; 10) Optionally substituted arylalkyl; 11) Optionally substituted 3- to 8-membered heterocycloalkyl; 12) Optionally substituted heteroaryl; 13) Optionally substituted heteroarylalkyl; 14) —N(R⁷)(R⁸); 15) —S(O)₂N(R⁷)(R⁸); 16) —N(R⁷)C(O)(R⁸); and 17) —N(R⁷)S(O)2(R⁸); R³ is selected from the group consisting of: 1) —NO₂; 2) Cyano; 3) —N(R⁷)(R⁸); 4) —N(R⁹)C(O)N(R⁷)(R⁸); 5) —N(R⁷)C(O)(R⁸); 6) —N(R⁷)C(O)₂(R⁸); 7) —N(R⁹)S(O)₂N(R⁷)(R⁸); 8) —N(R⁷)S(O)₂(R⁸); 9) —C(O)₂(R⁷); 10) —C(O)N(R⁷)(R⁸); 11) —C(O)N(R⁷)S(O)₂(R⁸); 12) —CH₂(O)C(O)₂(R⁷); 13) —CH₂(O)C(O)N(R⁷)(R⁸); 14) Optionally substituted —C₁-C₈ alkyl; 15) Optionally substituted —C₂-C₈ alkenyl; 16) Optionally substituted —C₂-C₈ alkynyl; 17) Optionally substituted —C₃-C₈ cycloalkyl; 18) Optionally substituted aryl; 19) Optionally substituted arylalkyl; 20) Optionally substituted 3- to 8-membered heterocycloalkyl; 21) Optionally substituted heteroaryl; and 22) Optionally substituted heteroarylalkyl; wherein R⁷, R⁸, and R⁹ are independently selected from the group consisting of hydrogen, —C₁-C₈alkyl, —C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, —CN, alkoxy, —CF₃, aryl, and heteroaryl; alternatively, R⁷ and R⁸ are taken together with the nitrogen atom to which they are attached to form a heterocyclic.
 2. The compound of claim 1, wherein

s selected from the following:

wherein each of the above shown groups is optionally substituted.
 3. The compound of claim 1, which is represented by Formula (VIIa), (VIIb), or (VIIc), or a pharmaceutically acceptable salt thereof:

wherein R¹, R², R³, and X¹ are as defined in claim
 1. 4. The compound of claim 1, which is represented by Formula (IIa) or (IIb), or a pharmaceutically acceptable salt thereof:

wherein R³, R⁴,

and X¹ are as defined in claim
 1. 5. The compound of claim 1, which is represented by Formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt thereof:

wherein R², R³, R⁴, and X¹ are as defined in claim
 1. 6. The compound of claim 1, which represented by Formula (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb) or a pharmaceutically acceptable salt thereof:

wherein R³ and R⁴ are as defined in claim
 1. 7. The compound of claim 1, which is selected from compounds of Formula (IIIa) or a pharmaceutically acceptable salt thereof:

wherein R³ and R⁴ are delineated for each compound in Table 1, TABLE 1 com- pound R³ R⁴ 1

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8. The compound of claim 1, which is selected from compounds of Formula (IIIb) or a pharmaceutically acceptable salt thereof:

wherein R³ and R⁴ are delineated for each compound in table 2, TABLE 2 com- pound R³ R⁴  61

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9. The compound of claim 1, which is selected from compounds of Formula (IVa) or a pharmaceutically acceptable salt thereof:

wherein R³ and R⁴ are delineated for each compound in Table 3, TABLE 3 com- pound R³ R⁴ 121

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10. The compound of claim 1, which is selected from compounds of Formula (IVb) or a pharmaceutically acceptable salt thereof:

wherein R³ and R⁴ are delineated for each compound in Table 4, TABLE 4 com- pound R³ R⁴ 181

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11. The compound of claim 1, which is selected from compounds of Formula (Va) or a pharmaceutically acceptable salt thereof:

wherein R³ and R⁴ are delineated for each compound in Table 5, TABLE 5 com- pound R³ R⁴ 241

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12. The compound of claim 1, which is selected from compounds of Formula (Vb) or a pharmaceutically acceptable salt thereof:

wherein R³ and R⁴ are delineated for each compound in Table 6, TABLE 6 com- pound R³ R⁴ 301

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13. The compound of claim 1, selected from the compounds set forth below, or a pharmaceutically acceptable salt thereof: Compound Structure  1

 2

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14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
 15. A method of treating a disease or condition selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis, bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver transplant associated graft versus host disease, congenital hepatic fibrosis, choledocholithiasis, diabetic nephropathy, focal segmental glomerulosclerosis, hypertensive nephrosclerosis, chronic transplant glomerulopathy, chronic interstitial nephritis, cardiac hypertrophy, heart attack, myocardial ischemia pyelonephritis, kidney fibrosis and glomerulonephritis, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim
 1. 